betadex and Acute-Pain

An intravenous bolus formulation of the non-steroidal anti-inflammatory drug diclofenac sodium has been developed using hydroxypropyl-β-cyclodextrin (HPβCD) as a solubility enhancer. HPβCD diclofenac (Dyloject(TM)) is available for use in adults in the USA for the management of mild to moderate pain, and as monotherapy or in combination with opioid analgesics for the management of moderate to severe pain. In two multicentre, phase III studies in adults with acute moderate to severe postoperative pain, HPβCD diclofenac significantly reduced pain intensity and the need for rescue medication compared with placebo. In these studies, the tolerability profile of HPβCD diclofenac was generally similar to that of placebo and adverse events were mostly mild to moderate in severity. Constipation, infusion-site pain and dizziness were the most frequently reported adverse reactions occurring numerically more frequently with HPβCD diclofenac than placebo. Therapy with HPβCD diclofenac does not appear to be associated with an increased risk of cardiovascular, renal or bleeding-related adverse events versus placebo. Thus, HPβCD diclofenac extends the treatment options currently available for the management of moderate to severe postoperative pain in adults.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Acute Pain; Anti-Inflammatory Agents, Non-Steroidal; beta-Cyclodextrins; Clinical Trials, Phase III as Topic; Diclofenac; Humans; Injections, Intravenous; Multicenter Studies as Topic; Pain Management

Long-term use of nonsteroidal anti-inflammatory drugs, including selective and nonselective cyclooxygenase inhibitors, has been suggested to be associated with cardiovascular (CV) safety risks. Data are limited regarding CV risks associated with short-term nonsteroidal anti-inflammatory drug use, including injectable formulations, although it has been suggested that even a single dose may increase CV adverse event (AE) risk. The objective of this study was to examine the CV safety of an injectable diclofenac formulation solubilized with hydroxypropyl-β-cyclodextrin (HPβCD) when given for ≤5days postoperatively.. A pooled analysis of CV AEs from 2 pivotal phase III clinical trials examining the efficacy and safety of intravenous (IV) HPβCD-diclofenac vs placebo and the active comparator ketorolac was conducted.. Postoperative, with treatment initiated in the postanesthesia care unit ≤6hours postsurgery.. Overall, 608 abdominal/pelvic and orthopedic surgery patients met inclusion criteria and received ≥1 study medication dose.. Patients received either HPβCD-diclofenac, ketorolac, or placebo via IV bolus injection every 6hours, for ≤5days postsurgery.. CV AEs, reported by study investigators, were evaluated through the treatment period and follow-up (≤37days after last study medication dose), and relative CV AE risks were estimated.. IV HPβCD-diclofenac was not associated with increased treatment-emergent CV AE incidence vs placebo (11.6% vs 12.2%; relative risk, 0.96 [95% confidence interval, 0.56-1.62]). Serious CV AEs as well as treatment-related AEs were uncommon, and there were no reports of myocardial infarction or cerebrovascular accident. CV AEs were uncommon during the follow-up period, occurring in 1.3%, 0%, and 1.4% of patients in the HPβCD-diclofenac, ketorolac, and placebo groups, respectively.. Although a longer duration follow-up study in a larger patient population would expand our understanding of potential CV risks, the present analysis suggests that postoperative use of HPβCD-diclofenac does not present an added CV safety risk over placebo.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Acute Pain; Adolescent; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; beta-Cyclodextrins; Cardiovascular Diseases; Diclofenac; Double-Blind Method; Excipients; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pain, Postoperative; Young Adult

Diclofenac is an effective and well-tolerated nonsteroidal anti-inflammatory drug (NSAID) frequently used in the treatment of acute pain. Marketed formulations for parenteral administration usually contain 75 mg/3 mL of diclofenac sodium, which provide limited dosing flexibility, and are usually given intramuscularly.. We present a randomized, double-blind, active comparator- and placebo-controlled, parallel-group phase III multicenter study, investigating efficacy and tolerability of a new 1 mL-volume formulation of diclofenac sodium (25, 50 or 75 mg) containing hydroxypropyl-β-cyclodextrin (HPβCD) as a solubility enhancer. This low-volume formulation allows subcutaneous (SC), in addition to intramuscular (IM) administration. Patients developing moderate-to-severe pain (≥ 50 mm on Visual Analogue Scale) after third molar extraction under local anesthesia were randomized to one of the 4 SC injections: 25 mg diclofenac HPβCD (n = 77), 50 mg diclofenac HPβCD (n = 76), 75 mg diclofenac HPβCD (n = 78), or placebo (n = 75).. Mean pain intensity difference at 1.5 hours postdose (primary endpoint) was higher in all diclofenac-treated groups than placebo group. The adjusted means (95% CI) were 36.5 (31.7 to 41.2) in diclofenac 25 mg group, 37.3 (32.6 to 42.1) in diclofenac 50 mg group, 37.7 (33.0 to 42.4) in diclofenac 75 mg group, and 12.3 (7.44 to 17.1) in placebo group. Both 25 and 50 mg doses of diclofenac produced significantly greater pain relief than placebo (P < 0.001 in both comparisons).. Single SC doses of diclofenac HPβCD of 25 and 50 mg are effective and well tolerated for relieving pain compared with placebo.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Acute Pain; Adolescent; Adult; Aged; Analysis of Variance; Anti-Inflammatory Agents, Non-Steroidal; beta-Cyclodextrins; Diclofenac; Dose-Response Relationship, Drug; Double-Blind Method; Excipients; Female; Humans; Injections, Subcutaneous; Male; Middle Aged; Sample Size; Visual Analog Scale; Young Adult